The study of the immune system has been greatly enhanced by the discovery of naturally occurring immunodeficient mouse strains. Distinct T and B cell deficient mutants (e.g., SCID, nude, beige, and x-linked) have been widely used in studying immune cell differentiation and as animal models for human disease (e.g., leukemia, solid tumors, and HIV infection). The goal of Phase I study is to generate transgenic immunodeficient mice (TIM) as improved hosts for experimental transplantation of human tissues. The major objective is to combine both T and NK cell deficiencies. This will eliminate not only B cell differentiation (due to lack of T(helper) function) but also the major cytotoxic killer cell functions responsible for rejecting foreign tissues. The strategy is based upon evidence that both T and NK cells share a common protein critical to their functional differentiation. The gene for this protein will be inactivated by insertional mutagenesis in embryonic stem (ES) cells, and its promoter will be used to direct tissue specific expression of diptheria toxin and thus cell ablation of T and NK cells. In Phase II study, a series of animal models will be developed based upon the long term engraftment of human tissues.